The vertebrate immune system protects the host from foreign pathogens such as virus, bacteria, parasite and fungus as well as senesced, damaged or diseased host cells. The host defense against foreign pathogens can be divided into three phases: innate immunity, “natural memory” and adaptive immunity.
Innate immunity is the first line of defense against foreign pathogens, which is active within minutes or hours after exposure to pathogen. The innate immunity is not antigen-specific; it is carried out by immune cells such as macrophages, mast cells, granulocytes (basophils, eosinophils, neutrophils), natural killer cells, and γδT cells, which recognize features that are common to many pathogens rather than specific antigens.
In contrast, the adaptive immunity is antigen-specific; it is carried out by antigen-specific T cells and B cells, in particular, follicular (FO) B cells, and takes days to two weeks to develop. T cells and FO B cells express antigen-specific receptors, T cell receptor (TCR) and B cell receptor (BCR), respectively, which are encoded by genes rearranged from the germline conformation.
In addition to being antigen-specific, the adaptive immunity differs from the innate immunity in its capability of generating immunological memory. The memory B and T cells are capable of launching a more rapid and more robust response against foreign antigens upon re-exposure to the same antigens.
The natural memory bridges the temporal gap between the innate immune response and the adaptive immune response; it is carried out by several components of the B and T cell lineages but does not generate lasting protective immunity for longer than a few days.
An important part of the natural memory immune response is the production of natural antibodies which have high cross-reactivity but low binding affinity against both microbial agents and some self antigens (Baumgarth et al., 1999; Baumgarth et al., 2000; Boes et al., 1998; Ochsenbein et al., 1999). The natural antibodies are encoded by rearranged antibody genes that have not undergone somatic mutation and are produced by marginal zone (MZ) B cells and peritoneal B1 cells. MZ B cells play a key role in the early response to pathogens in the bloodstream, whereas B1 cells in the pleural and peritoneal cavity play a key role in the response to pathogens introduced in the mucosal surfaces (see review by Lopes-Carvalho T and Kearney J F, 2004). Recent studies have suggested that B1 B cells and MZ B cells are also a source of auto-antibodies.
Even though B1 B cells and MZ B cells play a key role in natural memory immune response against foreign pathogens and are likely involved in autoimmune diseases involving auto-antibodies, the development, homeostasis and activation of these B cell subsets are only beginning to be elucidated (see reviews by Martin F and Kearney J F, 2000 and Srivastava B et al., 2005). Therefore, there remains a need in the art to better understand the biology of MZ and B1 B cells, in particular, their activation and the regulation of natural antibody production. Furthermore, there remains a need in the art to develop tools which allow for the modulation of the activities of MZ and B1 B cells, in particular, the production of natural antibodies, more particularly, the production of auto-reactive antibodies.